阅读说明：本技术 用于口服固体剂型的天然与有机的粘合剂组合物 (Natural and organic binder compositions for oral solid dosage forms ) 是由 F·施佩希特 M·尤尼斯 于 2018-03-14 设计创作，主要内容包括：本发明涉及一种不同的天然/有机的粘合剂的粘合剂组合物，以确保有效的片剂制造和批次间的一致性，同时避免在制造过程中，出现封盖或层压问题的风险。所述组合物包含组分的混合物，所述组分选自：a.按重量计约5％至约65％的瓜尔胶、黄原胶或其组合；b.按重量计约5％至约65％的阿拉伯胶；按重量计约5％至约65％的支链淀粉末、蜂蜜粉、龙舌兰粉末或分解的豌豆蛋白或前述的任何组合；d.按重量计约1％至约15％的天然植物纤维，所有重量百分比均基于粘合剂组合物的干重。(The present invention relates to a binder composition of different natural/organic binders to ensure efficient tablet manufacturing and lot-to-lot consistency while avoiding the risk of capping or lamination problems during manufacturing. The composition comprises a mixture of components selected from the group consisting of: a. from about 5% to about 65% by weight of guar gum, xanthan gum, or a combination thereof; b. about 5% to about 65% by weight of gum arabic; from about 5% to about 65% by weight of pullulan powder, honey powder, agave powder or decomposed pea protein or any combination of the foregoing; d. from about 1% to about 15% by weight of natural plant fibers, all weight percentages being based on the dry weight of the binder composition.)

1. A natural adhesive composition comprising a mixture of components a.through d. selected from: a. from about 5% to about 65% by weight of guar gum, xanthan gum, or a combination thereof; b. about 5% to about 65% by weight of gum arabic; from about 5% to about 65% by weight of pullulan powder, honey powder, agave powder or decomposed pea protein or any combination of the foregoing; d. from about 1% to about 15% by weight of natural plant fibers, all weight percentages being based on the dry weight of the binder composition.

2. A natural adhesive composition consisting of a mixture of components a.through d. selected from: a. from about 5% to about 65% by weight of guar gum, xanthan gum, or a combination thereof; b. about 5% to about 65% by weight of gum arabic; from about 5% to about 65% by weight of pullulan powder, honey powder, agave powder or decomposed pea protein or any combination of the foregoing; d. from about 1% to about 15% by weight of natural plant fibers, all weight percentages being based on the dry weight of the binder composition.

3. The natural binder composition according to claim 1 or 2, wherein the natural plant fiber is selected from the group consisting of apple fiber, cellulose powder, dehydrated fruit powder, rice powder or rice extract and mixtures thereof.

4. The natural binder composition of claim 3, wherein the dehydrated fruit powder is selected from the group consisting of banana powder, apple powder, pear powder, blueberry powder, cherry powder, cranberry powder, grape powder, peach powder, strawberry powder, raspberry powder, and mixtures of the foregoing.

5. The natural adhesive composition of any one of claims 1-4 wherein component (c.) is present in an amount of about 20% to about 40% by dry weight of the composition and is selected from pullulan powder, honey powder, agave powder, or decomposed pea protein.

6. The natural binder composition according to any one of claims 1-5, wherein component (a.) is selected from guar gum or xanthan gum, present in an amount of from about 20% to about 40% by dry weight of the composition.

7. The natural binder composition according to any one of claims 1-7, wherein (b.) acacia gum is present in an amount of about 20% to about 40% by dry weight of the composition.

8. The natural adhesive composition of any one of claims 1 to 8, wherein (d.) natural plant fiber is present in an amount of about 2% to about 8% by dry weight of the composition.

9. A method of producing a natural adhesive composition which is a mixture of components a.through d. selected from: from about 5% to about 65% by weight of guar gum, xanthan gum, or a combination thereof; b. about 5% to about 65% by weight of gum arabic; from about 5% to about 65% by weight of pullulan powder, honey powder, agave powder or decomposed pea protein or any combination of the foregoing; d. from about 1% to about 15% by weight of natural plant fibers, all weight percentages being provided based on the dry weight of the binder composition, and physically mixing until a homogeneous mixture is obtained.

10. The method according to claim 9, wherein the homogeneous mixture is further granulated.

11. Use of a natural adhesive composition according to any one of claims 1 to 8 in the manufacture of a solid dosage form formulation.

12. The use according to claim 11, wherein the solid dosage form formulation is a tablet, granule or pill.

13. A solid dosage form formulation comprising the binder composition of any one of claims 1 to 8 in an amount of about 1% to about 60% based on the total weight of the tablet (dry weight basis) of the tablet dosage form.

14. A solid dosage form formulation comprising the binder composition of any one of claims 1 to 9 in an amount of about 1% to about 40% w/w based on the total weight of the tablet (dry weight basis) of the tablet dosage form.

15. A solid dosage form formulation comprising the binder composition of any one of claims 1 to 9 in an amount of about 2% to about 20% w/w based on the total weight of the tablet (dry weight basis) of the tablet dosage form.

Technical Field

The present invention relates to the field of natural binding compositions for oral solid dosage forms. More particularly, the present invention relates to providing cohesiveness to the ingredients of a solid dosage form to form granules or tablets by a natural binder composition in the form of a premix. This ensures that the finished solid dosage form remains intact and can be labeled with a clean label.

Background

In the last few years, as consumer awareness of health and natural foods has increased, the use of natural additives in the food and pharmaceutical industries instead of artificial additives has increased and the diversity of their uses has also been of increasing interest. In terms of consumer preference, as it relates to pharmaceutical dosage forms and health functional foods, the happiness, health and eco-friendly factors in the production process are more and more emphasized, and thus, many products composed of natural components are being developed. As a result, the market share of these naturally composed products is also increasing. In recent years, the development of natural products has seen an incredible growth, which is essential for a variety of purposes.

However, it is understood that efforts to date have not been successful in formulating all-natural or substantially all-natural nutritional supplements (containing only or almost only certified organic/natural ingredients) in solid form. In particular, these developments do not allow tablets to ensure reliable characteristics, such as acceptable tablet hardness, good friability and/or acceptable dissolution of the active ingredient. In contrast, the use of natural ingredients can lead to undesirable processing characteristics such as reduced flowability, poor compressibility of the powder mixture, and batch-to-batch variation of the finished product.

In the pharmaceutical and food industries, many excipients are used in the manufacture of solid dosage forms. These excipients are widely involved in improving flowability, compression characteristics, binding and disintegration properties to increase the hardness of the tablet or enhance the processability of the solid dosage form. Excipients are used in solid dosage forms as inert substances to provide the required dose, uniformity and volume of the active ingredient for accurate administration, but in current solid dosage forms they generally have a multi-functional role, such as enhancing the bioavailability/solubility of the active ingredient, increasing patient acceptance and ensuring manufacturing effectiveness.

Tablets are the most accepted dosage form in pharmaceutical/nutritional products. Tablets are made by compressing a suitable powder mixture in a mold at a high compression force. The powder mixtures usually contain, in addition to the active ingredient, fillers, disintegrants, lubricants, glidants and binders. Industrial production of high quality tablets involves a tablet mixture having good homogeneity, flowability and compressibility. If the powder mixture does not have these properties, it must be pretreated, i.e. by granulation, otherwise direct compression can be carried out.

Two main methods of manufacturing tablets are known:

direct tabletting: the powder mixture is mixed over a period of time and may be directly compressed into tablets. This method is considered the most efficient and desirable method. The choice of binder is critical for direct compression.

The granulation technology comprises the following steps: including wet granulation and dry granulation/tableting methods in which the binder is added in liquid form and dry form, respectively. Some actives have poor flow and compressibility, in which case granules must be formed with acceptable flow and compressibility.

Binders are added to the tablet formulation to provide plasticity, as well as to increase interparticle bond strength and hardness in the tablet. Binders are substances that promote cohesion between the ingredients and hold the ingredients together to form the final tablet. It has been of continuing interest in the industry to systematically screen new natural materials for potential use as binders in solid dosage forms. This is because different binders or binder mixtures may be advantageous to successfully provide various mechanical strength and active release characteristics for different applications. To develop a solid dosage form, the correct choice of binder or binder mixture requires extensive knowledge of the binder properties to enhance the robustness of the formulation, as well as to enhance the interparticle forces between the various materials that make up the solid dosage form (particularly tablets).

To the best of the inventors' knowledge, there has not been available, prior to the present invention, any described or commercially available natural binder system in powder form, which is composed entirely or almost entirely of natural/certified organic components. Thus, there is a need for an improved adhesive that is composed entirely or almost entirely of natural/certified organic components. The existing artificial adhesives comprise: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), modified cellulose, pregelatinized starch powder, etc. Recent trends in the use of natural and non-toxic materials require the replacement of existing synthetic additives with natural additives.

Disclosure of Invention

In one embodiment of the present invention, a natural binder composition for use in direct compression or granulation techniques is provided. Preferably, the binder is present in powder form. A natural binder composition according to one embodiment of the invention comprises a mixture of components selected from a. a material selected from guar gum and xanthan gum or a combination thereof; b. acacia gum; c. a material selected from pullulan powder, honey powder, agave powder and decomposed pea protein or a combination thereof; d. natural plant fiber.

Guar (Guar Gum): also known as guarana, is a substance made of guar, with thickening and stabilising properties, which can be used in various industries, traditionally the food industry. The guar seeds are dehulled, ground and screened to obtain guar gum. It is usually produced as a free-flowing off-white powder. It is classified as galactomannan. In europe, guar gum has the european union food additive code E412.

Xanthan Gum (Xanthan Gum): also known as xanthan gum (xanthohan), is a polysaccharide produced from a series of simple sugars by a fermentation process. In europe, the european union food additive code for xanthan gum is E415.

Gum arabic (gummabic): also known as acacia gum (acaciagum), is a natural gum composed of hardened sap of various acacia species. Gum arabic is a complex mixture of glycoproteins and polysaccharides. It is the original source of the sugars arabinose and ribose, both of which were first found and isolated from the sugars and are named as such. It is edible, with E number E414.

Amylopectin powder: is an edible polysaccharide, mostly an odorless polymer, consisting of maltotriose units. As a food additive, its E number is E1204.

Honey powder: as an alternative to liquid honey in certain food applications, honey powder is based on honey with a carrier (such as maltodextrin, gluten-free, non-GMO, IP certified maltodextrin or other carrier) and is produced without any other additives. The final form is a free flowing powder with a fine to coarse crystalline structure and a light yellow to light meter color. Although its smell is mild and almost neutral, its taste provides a typical honey sweetness with a light honey aroma.

Agave powder: mixing the syrup with carrier (such as maltodextrin or cellulose carrier or other carrier).

Decomposed pea protein: is a natural plant material and has high nutritional property. It has an unusual amino acid profile compared to whey protein. Thus, it is a healthy protein, particularly suitable for vegetarians and people allergic to lactose and gluten. It is commercially available, for example, under the trade name

Preferred natural fibers are selected from: apple fiber, cellulose powder, dehydrated fruit powder, rice powder or rice extract and mixtures thereof. Preferred dehydrated fruit powders include banana powder, apple powder, pear powder, blueberry powder, cherry powder, cranberry powder, grape powder, peach powder, strawberry powder, raspberry powder, and mixtures thereof. The preferred powder sizes are 8 mesh (by USS # 8: minimum 90%; by USS # 30: maximum 25%) and 35 mesh: by USS # 35: the lowest is 90%. Although the amount of calcium stearate added is 0.5% at the maximum, it is further preferable to use an untreated powder to prevent caking. In some cases, the natural fibers may contain up to 600ppm sodium sulfite or SO₂To inhibit enzymatic and non-enzymatic browning.The rice extract, also called red yeast rice extract, is a substance extracted from yeast-fermented rice.

In another embodiment, the present invention provides a method of producing a natural adhesive composition that is a mixture of components selected from the group consisting of: a. a material selected from the group consisting of guar, xanthan, and combinations thereof; b. acacia gum; c. a material selected from the group consisting of pullulan powder, honey powder, agave powder, hydrolyzed pea protein, and combinations thereof; d. providing natural plant fiber and physically mixing without any chemical reaction process.

It has been found that the natural binder composition according to the invention improves the flowability and compressibility of the entire compressed powder mixture and ensures efficient manufacture of tablets with constant weight, uniform strength and batch-to-batch consistency. Preferably, the natural binder composition according to the invention is present in the tablet in an amount of 1% to 60% w/w (based on dry weight) of the total weight of the tablet dosage form, more preferably 1% to 40% w/w. In particular, the present invention has a positive effect on tablet hardness: the 3% content of the composition of the invention in the formulation already has a higher value than a tablet with the same (or even a higher content) dry binder, such as hydroxypropyl cellulose. Due to this fact, the present invention is an excellent natural/organic binder with good properties and can also be used as a substitute for conventional dry binders.

Detailed Description

According to one embodiment of the invention, the natural adhesive composition comprises a mixture of components selected from: a. from about 5% to about 65% by weight of guar gum, xanthan gum, or a combination thereof; b. about 5% to about 65% by weight of gum arabic; from about 5% to about 65% by weight of pullulan powder, honey powder, agave powder or decomposed pea protein or any combination of the foregoing; d. from about 1% to about 15% by weight of natural plant fibers, all weight percentages being based on the dry weight of the binder composition.

According to another embodiment of the invention, the natural adhesive composition consists of a mixture of components selected from: from about 5% to about 65% by weight of guar gum, xanthan gum, or a combination thereof; b. about 5% to about 65% by weight of gum arabic; from about 5% to about 65% by weight of pullulan powder, honey powder, agave powder or decomposed pea protein or any combination of the foregoing; from about 1% to about 15% by weight of natural plant fiber, all weight percentages being based on the dry weight of the binder composition.

The natural binder composition may be used in the tablet in an amount of about 1 to about 60% w/w, more preferably about 1 to about 40% w/w, most preferably about 3 to about 30% w/w, based on the total weight of the tablet (on a dry weight basis).

The amount of amylopectin flour, honey flour, agave powder or decomposed pea protein, or any combination of the foregoing, which is used as the main natural binder in the binder composition according to the invention, is within about 5% to about 65% by weight of the binder composition (on a dry weight basis). The amylopectin powder may be organically certified and/or USP/NF compliant. Preferred amounts are from about 20% to about 40% by weight of the adhesive composition (dry basis).

The amount of gum arabic used as the secondary natural binder in the binder compositions according to the present invention is within about 5% to about 65% by weight of the binder composition (on a dry basis). The grade of gum arabic may be organically certified and/or compliant with the Food Chemical Code (FCC). Preferred amounts are from about 20% to about 45% (by dry weight) by weight of the adhesive composition.

The amount of guar gum, xanthan gum, or a combination thereof used as the third natural binder in the binder composition according to the present invention is within about 5% to about 65% by weight of the binder composition (on a dry weight basis). The guar or xanthan gum grades may be organically certified and/or certified by the Food Chemical Code (FCC). Preferred amounts are from about 20% to about 40% by weight of the adhesive composition (dry basis).

The vegetable fibres as described above are added to the compound according to the invention as a natural flow aid in an amount of about 1% to about 15% by weight of the binder composition (dry weight basis). The grade of the fiber may be organically certified or conventional. Preferred amounts are from about 2% to about 8% (by dry weight) by weight of the adhesive composition.

According to another embodiment of the present invention, there is provided a method of producing a natural adhesive composition that is a mixture of components selected from the group consisting of: a material selected from the group consisting of guar, xanthan, and combinations thereof; b. acacia gum; c. a material selected from the group consisting of pullulan powder, honey powder, agave powder, hydrolyzed pea protein, and combinations thereof; d. natural plant fibers are provided and physically mixed until a homogeneous mixture is obtained. The mixer is preferably a V-type powder mixer, but may be any other mixer suitable for mixing dry powder.

Optionally, the dry powder mixture is further granulated by slowly adding sufficient water until granules form, and then sieving and drying the granules so obtained. The granulation is preferably carried out in a planetary mixer. Granulation is intended to increase the flowability and compressibility of the dry powder mixture and is dust-free. Alternatively, other granulation methods may be applied, such as spray granulation or roller compaction.

According to yet another example, the present invention provides a solid dosage form formulation comprising the binder composition of claim 1 in an amount of from about 1% to about 60%, preferably from about 1% to about 40%, more preferably from about 2% to about 20%, for example from about 3% to about 5% w/w, based on the total weight (on a dry weight basis) of the tablets in the tablet formulation.

Hereinafter, the present invention will be described in detail with reference to the following examples. It should be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Examples of the invention

The following examples 1-15 illustrate the invention. All percentages are by weight of the composition.

Example 1:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	30
Arabic gum	FCC/organic	35
			Amylopectin powder	USP/NF/organic	30
Apple fiber	Organic compounds	5

The dry adhesive composition is produced by mixing the ingredients in a type V powder mixer until a homogeneous mixture is obtained. The dry powder mixture was also granulated in a planetary mixer by slowly adding sufficient water until granules were formed. The granules were then sieved through a 1-2mm sieve and dried in an oven at 30 ℃ until the moisture content of the granules was below 5%. The dried granules were sieved again through the same sieve.

In the following examples, dry adhesive compositions were produced as in example 1, but, as in example 1, with different ingredients or different amounts per weight of ingredients:

example 2:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	25
Arabic gum	FCC/organic	35
			Amylopectin powder	USP/NF/organic	30
Apple fiber	Organic compounds	10

Example 3:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	30
Arabic gum	FCC/organic	35
			Amylopectin powder	USP/NF/organic	30
Cellulose powder	FCC					5

Example 4:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	30
Arabic gum	FCC/organic	35
			Amylopectin powder	USP/NF/organic	30
Banana powder	Organic compounds	5

Example 5:

example 6:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	35
Arabic gum	FCC/organic	35
			Amylopectin powder	USP/NF/organic	20
Apple fiber	Organic compounds	10

Example 7:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	40
Arabic gum	FCC/organic	25
			Amylopectin powder	USP/NF/organic	30
Rice concentrate	FCC/organic	5

Example 8:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	30
Arabic gum	FCC/organic	35
			Amylopectin powder	USP/NF/organic	30
Rice extract	FCC/organic	5

Example 9:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	30
Arabic gum	FCC/organic	30
			Amylopectin powder	USP/NF/organic	30
Rice concentrate	FCC/organic	10

Example 10:

auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	25
Arabic gum	FCC/organic	35
			Amylopectin powder	USP/NF/organic	30
Banana powder	FCC/organic	10

Example 11

Test series were defined to verify the effect of the present invention on tablet hardness. Several formulations with different binder contents were investigated in terms of tablet hardness they provide.

The tablets were compressed with a standard round tool having a diameter of 10mm and a thickness of 5mm and then engraved. For characterization, tablets were tested for tablet hardness (according to ph. eur.2.9.8).

The formulations prepared are illustrated in tables 1-5 below. All percentages are by weight of the composition.

Adhesive formulation 1 (comparative): containing 3% of HPC

The components:	％w/w
		microcrystalline cellulose	66.9
Dicalcium phosphate	29.1
		Magnesium stearate	1
HPC	3

Adhesive formulation 2 (comparative): containing 5% of HPC

The components:	％w/w
		microcrystalline cellulose	65.5
Dicalcium phosphate	28.5
		Magnesium stearate	1
HPC	5

Adhesive formulation 3 (inventive): natural binder with 3% premix

The components:	％w/w
		microcrystalline cellulose	66.9
Dicalcium phosphate	29.1
		Magnesium stearate	1
Inventive premixed binders	3

In the following examples, dry adhesive compositions were produced as in example 1, but, as in example 1, with different ingredients or different amounts per weight of ingredients:

example 12

Auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	30
Arabic gum	FCC/organic	30
			Agave powder	USDA/NOP/ORGANIC	30
Rice concentrate	FCC/organic	10

Example 13

Example 14

Auxiliary materials:	grade:	％w/w
			guar gum	21CFR 184.1339/organic	30
Arabic gum	FCC/organic	30
			Decomposed pea protein	Organic compounds	30
Rice concentrate	FCC/organic	10

Example 15:

the binder formulations described above were used to prepare tablets as described in binder formulations 1-3. Tablets were studied for tablet hardness. At laboratory scaleDifferent study formulations were compressed on a single station tablet press. After the compaction process, according to Ph.The Eur tested the hardness of the tablets with 2.9.8 (tablet hardness tester) of PTB 111E.

The equipment used was:

the parameters used were:

dosage forms	Tablet formulation
		Shape of	Biconvex, circular
Diameter of	10mm
		Compressive force	25kN
Depth of filling	8mm

Fig. 1 illustrates the results of a tablet hardness survey. Surprisingly, a tablet coating of higher tablet hardness can be provided compared to prior art binder compositions (using the same amount of binder).

Fig. 2 shows that the premix Binder (Binder-Pre-Mix) composition of the present invention has different contents of honey powder, agave powder or decomposed pea protein in place of amylopectin powder compared with tablet hardness in the formulation.

Accordingly, it is to be understood that the embodiments of the invention herein described are merely illustrative of the application of the principles of the invention. Reference herein to details of the illustrated embodiments is not intended to limit the scope of the claims, which themselves recite those features regarded as essential to the invention.